Photoreceptor rescue and toxicity induced by different calpain inhibitors
Photoreceptor rescue and toxicity induced by different calpain inhibitors
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DOI：
10.1111/j.1471-4159.2010.06983.x
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发表时间：
2010-11-01
影响因子：
4.7
通讯作者：
Ekstrom, Per
中科院分区：
文献类型：
--
作者：
Paquet-Durand, Francois;Sanges, Daniela;Ekstrom, Per
光感受器退化是一组遗传性致盲疾病的标志，统称为视网膜色素变性（RP），是人类失明的主要原因。RP是目前无法治疗的和潜在的神经退行性机制在很大程度上是未知的，即使遗传原因往往是确定的。钙蛋白酶型蛋白酶的激活可能在包括视网膜在内的各种神经元组织中的细胞死亡中起重要作用。因此，我们测试了两种不同的钙蛋白酶抑制剂在视网膜变性（rd 1）人同源RP小鼠模型中预防细胞死亡的功效。药理学抑制rd1器官型视网膜外植体中钙蛋白酶活性对感光细胞活力的影响不明确。钙蛋白酶抑制剂XI在短时间内（16小时）应用时具有保护作用，但在几天内使用时在野生型和rd1视网膜中表现出相当大的毒性水平。相比之下，高度特异性的钙蛋白酶抑制剂钙蛋白酶抑制剂肽在短期和长期暴露后减少体外感光细胞死亡，这种作用在通过玻璃体内注射体内应用后也是明显的。这些研究结果强调了钙蛋白酶激活对感光细胞死亡的重要性，但也为感光细胞的生存，并建议使用高度特异性的钙蛋白酶抑制剂，以防止或延迟RP。
P>Photoreceptor degeneration is the hallmark of a group of inherited blinding diseases collectively termed retinitis pigmentosa (RP); a major cause of blindness in humans. RP is at present untreatable and the underlying neurodegenerative mechanisms are largely unknown, even though the genetic causes are often established. The activation of calpain-type proteases may play an important role in cell death in various neuronal tissues, including the retina. We therefore tested the efficacy of two different calpain inhibitors in preventing cell death in the retinal degeneration (rd1) human homologous mouse model for RP. Pharmacological inhibition of calpain activity in rd1 organotypic retinal explants had ambiguous effects on photoreceptor viability. Calpain inhibitor XI had protective effects when applied for short periods of time (16 h) but demonstrated substantial levels of toxicity in both wild-type and rd1 retina when used over several days. In contrast, the highly specific calpain inhibitor calpastatin peptide reduced photoreceptor cell death in vitro after both short and prolonged exposure, an effect that was also evident after in vivo application via intravitreal injection. These findings highlight the importance of calpain activation for photoreceptor cell death but also for photoreceptor survival and propose the use of highly specific calpain inhibitors to prevent or delay RP.